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General Information About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide, and it has the fourth highest mortality rate among cancers in women.[1] Most cases of cervical cancer are preventable by routine screening and by treatment of precancerous lesions. As a result, most of the cervical cancer cases are diagnosed in women who live in regions with inadequate screening protocols.

Incidence and Mortality

Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2016:[2]

New cases: 12,990.

Deaths: 4,120.

Anatomy

The uterine cervix is contiguous with the uterine body, and it acts as the opening to the body of the uterus. The uterine cervix is a cylindrical, fibrous organ that is an average of 3 to 4 cm in length. The portio of the cervix is the part of the cervix that is visible on vaginal inspection. The opening of the cervix is termed the external os. The os is the beginning of the endocervical canal, which forms the inner aspect of the cervix. At the upper aspect of the endocervical canal is the internal os, a narrowing of the endocervical canal. The narrowing marks the transition from the cervix to the uterine body. The endocervical canal beyond the internal os is termed the endometrial canal.

The cervix is lined by two types of epithelial cells: squamous cells at the outer aspect, and columnar, glandular cells along the inner canal. The transition between squamous cells and columnar cells is an area termed the squamo-columnar junction. Most of precancerous and cancerous changes arise in this zone.

Pathogenesis

Cervical carcinoma has its origins at the squamous-columnar junction; it can involve the outer squamous cells, the inner glandular cells, or both. The precursor lesion is dysplasia: cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ, which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in patients with untreated in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.

Risk Factors

Human papillomavirus (HPV) infection

HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.

More than 6 million women in the United States are estimated to be infected with HPV. Transient HPV infection is common, particularly in young women,[3] while cervical cancer is rare. The persistence of an HPV infection leads to increased risk of developing precancerous and cancerous lesions.[4,5]

The strain of HPV infection is also important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN.[6,7,8] Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytologic screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.[9,10,11]

There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed towards HPV-naïve girls and young women, and although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented.[12] (Refer to the PDQ summary on Cervical Cancer Prevention for more information.)

Given the relevance of HPV status in assessing risk, studies limited to HPV-positive women in cases and the control groups provide the most information on the additional cofactors that may promote progression of HPV infection to precancerous and cancerous lesions.

(Refer to the PDQ summary on Cervical Cancer Prevention for more information.)

Clinical Features

Early cervical cancer may not cause noticeable signs or symptoms.

Possible signs and symptoms of cervical cancer include the following:

Vaginal bleeding.

Unusual vaginal discharge.

Pelvic pain.

Dyspareunia.

Postcoital bleeding.

Diagnosis

The following procedures may be used to diagnose cervical cancer:

History and physical exam.

Pelvic exam.

Cervical cytology (Pap smear).

HPV test.

Endocervical curettage.

Colposcopy.

Biopsy.

HPV testing

Cervical cytology (Pap smear) has been the mainstay of cervical cancer screening since its introduction. However, molecular techniques for the identification of HPV DNA are highly sensitive and specific. Current screening options include the following:

Cytology alone.

Cytology and HPV testing.

HPV testing is suggested when it is likely to successfully triage patients into low- and high-risk groups for a high-grade dysplasia or greater lesion.

HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique.[15] The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost.[15]

HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines.[15,16,17]

Other studies show that patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have CIN or microinvasive histopathology on biopsy.[6,18,19,20] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer.[21]

For women older than 30 years who are more likely to have persistent HPV infection, HPV typing can successfully triage women into high- and low-risk groups for CIN 3 or worse disease. In this age group, HPV DNA testing is more effective than cytology alone in predicting the risk of developing CIN 3 or worse.[22] Other studies have shown the effectiveness of a primary HPV DNA–screening strategy with cytology triage over the previously used cytology-based screening algorithms.[23,24]

Prognostic Factors

The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. More than 90% of cervical cancer cases can be detected early through the use of the Pap test and HPV testing.[25] Pap and HPV testing are not performed on approximately 33% of eligible women, which results in a higher-than-expected death rate.

Clinical stage

Clinical stage as a prognostic factor is supplemented by several gross and microscopic pathologic findings in surgically treated patients.

Evidence (clinical stage and other findings):

In a large, surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that most prominently predicted for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being the most important and reproducible.[26,27]

In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than with clinical or histologic stage.[28]

A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:[29]

Periaortic and pelvic lymph node status.

Tumor size.

Patient age.

Performance status.

Bilateral disease.

Clinical stage.

The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.

It is controversial whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[30] Several population-based and retrospective studies show a worse outcome for patients with adenocarcinoma, with an increase in distant metastasis noted, when compared with those with squamous histology.[31,32,33,34] Reports conflict about the effect of adenosquamous cell type on outcome.[35,36] One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis.[37]

In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to the lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA.[38] A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[38]

GOG studies have indicated that prognostic factors vary depending on whether clinical or surgical staging are utilized and with different treatments. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. To-date, stage, tumor grade, race, and age are uncertain prognostic factors in studies utilizing chemoradiation.[39]

Other prognostic factors

Other prognostic factors that may affect outcome include the following:

Human immunodeficiency virus (HIV) status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.[40]

C-myc overexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis.[41]

Number of cells in S phase: The number of cells in S phase may also have prognostic significance in early cervical carcinoma.[42]

HPV-18 DNA: HPV-18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.[43,44]

A polymorphism in the Gamma-glutamyl hydrolase enzyme, which is related to folate metabolism, has been shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.[45]

Follow-up After Treatment

High-quality studies are lacking, and the optimal treatment follow-up for patients after treatment for cervical cancer is unknown. Retrospective studies have shown that patients who recur are most likely to do so within the first 2 years.[46] As a result, most guidelines suggest routine follow-up every 3 to 4 months for the first 2 years, followed by evaluations every 6 months. Most recurrences are diagnosed secondary to new patient symptoms and signs,[47,48] and the usefulness of routine testing including a Pap smear and chest x-ray is unclear.

Follow-up should be centered around a thorough history and physical examination with a careful review of symptoms; imaging should be reserved for evaluation of a positive finding. Patients should be asked about possible warning signs, including the following:

Abdominal pain.

Back pain.

Painful or swollen leg.

Problems with urination.

Cough.

Fatigue.

The follow-up examination should also screen for possible complications of previous treatment because of the multiple modalities (surgery, chemotherapy, and radiation) that patients often undergo during their treatment.

Related Summaries

Other PDQ summaries containing information related to cervical cancer include the following:

Cellular Classification of Cervical Cancer

Squamous cell (epidermoid) carcinoma comprises approximately 90% of cervical cancers, and adenocarcinoma comprises approximately 10% of cervical cancers. Adenosquamous and small cell carcinomas are relatively rare. Primary sarcomas of the cervix and primary and secondary malignant lymphomas of the cervix have also been reported.

Stage Information for Cervical Cancer

Carcinoma of the cervix can spread via local invasion, the regional lymphatics, or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.

Pretreatment surgical staging is the most accurate method to determine the extent of disease,[1] but there is little evidence to demonstrate overall improved survival with routine surgical staging; the staging is usually performed only as part of a clinical trial. Pretreatment surgical staging in bulky but locally curable disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by computed tomography (CT) scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.

Tests and procedures to evaluate the extent of the disease include the following:

The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer have designated staging to define cervical cancer; the FIGO system is most commonly used.[3,4]

b The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. Vascular space invasion should not alter the staging.

I

The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded).

IA

Invasive cancer identified only microscopically. (All gross lesions even with superficial invasion are Stage IB cancers.) Invasion is limited to measured stromal invasion with a maximum depth of 5 mmb and no wider than 7 mm.

The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer-free space between the tumor and pelvic sidewall. The tumor involves the lower third of the vagina. All cases of hydronephrosis or nonfunctioning kidney should be included unless they are known to be due to other causes.

IIIA

Involvement of the lower vagina but no extension onto pelvic sidewall.

Treatment Option Overview for Cervical Cancer

Patterns-of-care studies clearly demonstrate the negative prognostic effect of increasing tumor volume and spread pattern.[1] Treatment, therefore, may vary within each stage as the individual stages are currently defined by Féderation Internationale de Gynécologie et d'Obstétrique (FIGO).

Table 5. Standard Treatment Options for Cervical Cancer

Stage ( FIGO Staging Criteria)

Standard Treatment Options

FIGO = Féderation Internationale de Gynécologie et d'Obstétrique.

In situ carcinoma of the cervix (this stage is not recognized by FIGO)

Five randomized, phase III trials (GOG-85, RTOG-9001, GOG-120, GOG-123, and SWOG-8797) have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[2,3,4,5,6] while one trial examining this regimen demonstrated no benefit.[7] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease who were found to have poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery.

Although the positive trials vary in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.

Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[2,3,4,5,6]

In Situ Cervical Cancer Treatment

Consensus guidelines have been issued for managing women with cervical intraepithelial neoplasia or adenocarcinoma in situ.[1] Properly treated, tumor control of in situ cervical carcinoma should be nearly 100%. Either expert colposcopic-directed biopsy or cone biopsy is required to exclude invasive disease before therapy is undertaken. A correlation between cytology and colposcopic-directed biopsy is also necessary before local ablative therapy is done. Unrecognized invasive disease treated with inadequate ablative therapy may be the most common cause of failure.[2] Failure to identify the disease, lack of correlation between the Pap smear and colposcopic findings, adenocarcinoma in situ, or extension of disease into the endocervical canal makes a laser, loop, or cold-knife conization mandatory.

The choice of treatment depends on the extent of disease and several patient factors, including age, cell type, desire to preserve fertility, and medical condition.

Standard Treatment Options forIn Situ Cervical Cancer

Standard treatment options for in situ cervical cancer include the following:

Hysterectomy is the standard treatment for patients with adenocarcinoma in situ. The disease, which originates in the endocervical canal, may be more difficult to completely excise with a conization procedure. Conization may be offered to select patients with adenocarcinoma in situ who desire future fertility.

Conization

When the endocervical canal is involved, laser or cold-knife conization may be used for selected patients to preserve the uterus, avoid radiation therapy, and more extensive surgery.[6]

In selected cases, the outpatient LEEP may be an acceptable alternative to cold-knife conization. This procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization.[7,8,9] However, controversy exists about the adequacy of LEEP as a replacement for conization; LEEP is unlikely to be sufficient for patients with adenocarcinoma in situ.[10]

Evidence (conization using LEEP):

A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia.[6]

Two case reports suggested that the use of LEEP in patients with occult invasive cancer led to an inability to accurately determine depth of invasion when a focus of the cancer was transected.[11]

Hysterectomy for postreproductive patients

Hysterectomy is standard therapy for women with cervical adenocarcinoma in situ, because of the location of the disease in the endocervical canal and the possibility for skip lesions in this region, making margin status a less reliable prognostic factor. However, the effect of hysterectomy compared with conservative surgical measures on mortality has not been studied. Hysterectomy may be performed for squamous cell carcinoma in situ if conization is not possible because of previous surgery, or if positive margins are noted after conization therapy. Hysterectomy is not an acceptable front-line therapy for squamous carcinoma in situ.[12]

Internal radiation therapy for medically inoperable patients

For medically inoperable patients, a single intracavitary insertion with tandem and ovoids for 5,000 mg hours (80 Gy vaginal surface dose) may be used.[13]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage 0 cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Bloss JD: The use of electrosurgical techniques in the management of premalignant diseases of the vulva, vagina, and cervix: an excisional rather than an ablative approach. Am J Obstet Gynecol 169 (5): 1081-5, 1993.

Stage IA Cervical Cancer Treatment

If the depth of invasion is less than 3 mm, no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients who wish to preserve fertility.[1]

Total hysterectomy

If the depth of invasion is less than 3 mm, which is proven by cone biopsy with clear margins,[2] no vascular or lymphatic channel invasion is noted, and the frequency of lymph-node involvement is sufficiently low, lymph-node dissection at the time of hysterectomy is not required. Oophorectomy is optional and should be deferred for younger women.

For patients with tumor invasion between 3 mm and 5 mm, modified radical hysterectomy with pelvic-node dissection has been recommended because of a reported risk of lymph-node metastasis of as much as 10%.[2] Radical hysterectomy with node dissection may also be considered for patients for whom the depth of tumor invasion was uncertain because of invasive tumor at the cone margins.

Other Treatment Options

Radical trachelectomy.

Intracavitary radiation therapy.

Radical trachelectomy

Patients with stages IA2 to IB disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. Most centers utilize the following criteria for patient selection:

Desire for future pregnancy.

Age younger than 40 years.

Presumed stage IA2 to IB1 disease and a lesion size no greater than 2 cm.

Preoperative magnetic resonance imaging that shows a margin from the most distal edge of the tumor to the lower uterine segment.

Squamous, adenosquamous, or adenocarcinoma cell types.

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[3,4,5,6,7]

Intracavitary radiation therapy

Intracavitary radiation therapy is a treatment option when palliative treatment is appropriate because of other medical conditions and for women who are not surgical candidates.

If the depth of invasion is less than 3 mm and no capillary lymphatic space invasion is noted, and the frequency of lymph-node involvement is sufficiently low, external-beam radiation therapy is not required. One or two insertions with tandem and ovoids for 6,500 mg to 8,000 mg hours (100–125 Gy vaginal surface dose) are recommended.[8]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IA cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy.

The size of the tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1]

Either radiation therapy or radical hysterectomy and bilateral lymph–node dissection results in cure rates of 85% to 90% for women with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) stages IA2 and IB1 small-volume disease. The choice of either treatment depends on patient factors and available local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival rates when comparing radiation therapy with radical hysterectomy.[2]

In stage IB2, for tumors that expand the cervix more than 4 cm, the primary treatment should be concomitant chemotherapy and radiation therapy.[3]

Radiation therapy with concomitant chemotherapy

Concurrent, cisplatin-based chemotherapy with radiation therapy is the standard of care for women who require radiation therapy for treatment of cervical cancer.[4,5,6,7,8,9,10] Radiation therapy protocols for patients with cervical cancer have historically used dosing at two anatomical points, termed point A and point B, to standardize the doses received. Point A is defined as 2 cm from the external os, and 2 cm lateral, relative to the endocervical canal. Point B is also 2 cm from the external os, and 5 cm lateral from the patient midline, relative to the bony pelvis. In general, for smaller tumors, the curative-intent dose for point A is around 70 Gy, whereas for larger tumors, the point A dose may approach 90 Gy.

Evidence (radiation with concomitant chemotherapy):

Three randomized, phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy,[4,5,6,7] while one trial that examined this regimen demonstrated no benefit.[8] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.

Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.

The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.

Standard radiation therapy for cervical cancer includes brachytherapy after external-beam radiation therapy (EBRT). Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as components of cervical cancer treatment.[11,12]

Evidence (brachytherapy):

In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[13,14,15][Level of evidence: 1iiDii]

Surgery after radiation therapy may be indicated for some patients with tumors confined to the cervix that respond incompletely to radiation therapy or for patients whose vaginal anatomy precludes optimal brachytherapy.[16]

Pelvic node disease

The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[17] Patients who underwent extraperitoneal lymph–node sampling had fewer bowel complications than those who had transperitoneal lymph–node sampling.[18,19,20] Patients with close vaginal margins (<0.5 cm) may also benefit from pelvic radiation therapy.[21]

Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy

Radical hysterectomy and bilateral pelvic lymphadenectomy may be considered for women with stages IB to IIA disease.

Evidence (radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy):

An Italian group randomly assigned 343 women with stage IB and IIA cervical cancer to surgery or radiation therapy. The radiation therapy included EBRT and one Cs-137 LDR insertion, with a total dose to point A from 70 to 90 Gy (median 76 Gy). Patients in the surgery arm underwent a class III radical hysterectomy, pelvic lymphadenectomy, and selective, para-aortic lymph–node dissection. Adjuvant radiation therapy was given to patients with high-risk pathologic features in the uterine specimen or positive lymph nodes. Adjuvant radiation therapy was EBRT to a total dose of 50.4 Gy over 5 to 6 weeks.[2][Level of evidence: 1iiA]

The primary outcome was OS at 5 years, with secondary measures of rate of recurrence and complications. With a median follow-up of 87 months, OS was the same in both groups at 83% (hazard ratio [HR], 1.2; confidence interval [CI], 0.7–2.3; P = .8).

Complications were highest among the patients who received adjuvant radiation after surgery.

In general, radical hysterectomy should be avoided in patients who are likely to require adjuvant therapy.

Adjuvant radiation therapy post surgery

Based on recurrence rates in previous clinical trials, two classes of recurrence risk have been defined. Patients with a combination of large tumor size, lymph vascular space invasion, and deep stromal invasion in the hysterectomy specimen are deemed to have intermediate-risk disease. These patients are candidates for adjuvant EBRT.[22] Patients whose pathology shows positive margins, positive parametria, or positive lymph nodes are high-risk candidates for recurrence.

Evidence (adjuvant radiation therapy post surgery):

The Gynecologic Oncology Group (GOG) compared adjuvant radiation therapy alone with radiation therapy plus cisplatin plus fluorouracil (5-FU) after radical hysterectomy for patients in the high-risk group. Postoperative patients were eligible if their pathology showed any one of the following: positive parametria, positive margins, or positive lymph nodes. Patients in both arms received 49 Gy to the pelvis. Patients in the experimental arm also received cisplatin (70 mg/m2) and a 96-hour infusion of 5-FU (1000 mg/m2 /d every 3 weeks for four cycles); the first two cycles were concurrent with the radiation therapy.[6][Level of evidence: 1iiA]

There were 268 patients evaluated with a primary endpoint of OS. The study results were reported early because of the positive results in other trials of concomitant cisplatin and radiation therapy.

As expected, grade 4 toxicity was more common in the chemotherapy plus radiation therapy group, with hematologic toxicity predominating.

Radical surgery has been performed for small lesions, but the high incidence of pathologic factors leading to postoperative radiation with or without chemotherapy make primary concomitant chemotherapy and radiation a more common approach in patients with larger tumors. Radiation in the range of 50 Gy administered for 5 weeks plus chemotherapy with cisplatin with or without 5-FU should be considered in patients with a high risk of recurrence.

Para-aortic nodal disease

After surgical staging, patients found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[23] Treatment of patients with unresected para-aortic nodes with extended-field radiation therapy and chemotherapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3.[18] A single study (RTOG-7920) showed a survival advantage in patients with tumors larger than 4 cm who received radiation therapy to para-aortic nodes without histologic evidence of disease.[24] Toxic effects were greater with para-aortic radiation therapy than with pelvic radiation therapy alone but were mostly confined to patients with previous abdominopelvic surgery.[24] The use of intensity-modulated radiation therapy (IMRT) may minimize the effects to the small bowel usually associated with this treatment.[25]

Other Treatment Options

Radical trachelectomy.

Neoadjuvant chemotherapy.

Radiation therapy alone.

IMRT.

Radical trachelectomy

Patients with presumed early-stage disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. The patient selection differs somewhat between groups, however, general criteria include the following:

Desire for future pregnancy.

Age younger than 40 years.

Presumed stage IA2 to IB1 disease and a lesion size no greater than 2 cm.

Preoperative magnetic resonance imaging that shows a margin from the most distal edge of the tumor to the lower uterine segment.

Squamous, adenosquamous, or adenocarcinoma cell types.

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[26,27,28,29,30]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[31,32,33,34,35] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[36] As a result, the control arm utilized radiation therapy alone. Although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary endpoint, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Radiation therapy alone

External-beam pelvic radiation therapy combined with two or more intracavitary brachytherapy applications is appropriate therapy for patients with stage IA2 and IB1 lesions. For patients with stage IB2 and larger lesions, radiosensitizing chemotherapy is indicated. The role of radiosensitizing chemotherapy in patients with stage IA2 and IB1 lesions is untested. However, it may prove beneficial in certain cases.

IMRT

IMRT is a radiation therapy technique that allows for conformal dosing of target anatomy while sparing neighboring tissue. Theoretically, this technique should decrease radiation therapy–related toxicity, but this could come at the cost of decreased efficacy if tissue is inappropriately excluded from the treatment field. Several institutions have reported their experience with IMRT for postoperative adjuvant therapy in patients with intermediate-risk and high-risk disease after radical surgery.[37,38,39] The Radiation Therapy Oncology Group (RTOG) has closed accrual for a phase II trial (RTOG-0418 [NCT00331760]) that is evaluating the use of IMRT in patients with both cervical and endometrial cancers who require adjuvant radiation therapy.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stages IIB, III, and IVA Cervical Cancer Treatment

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] Survival and local control are better with unilateral rather than bilateral parametrial involvement.[2] Patterns-of-care studies in stages IIIA and IIIB patients indicate that survival is dependent on the extent of the disease, with unilateral pelvic wall involvement predicting a better outcome than bilateral involvement, which in turn predicts a better outcome than involvement of the lower third of the vaginal wall.[2] These studies also reveal a progressive increase in local control and survival paralleling a progressive increase in paracentral (point A) dose and use of intracavitary treatment. The highest rate of central control was seen with paracentral (point A) doses of more than 85 Gy.[3]

Strong consideration should be given to the use of intracavitary radiation therapy and external-beam radiation therapy (EBRT) to the pelvis combined with cisplatin or cisplatin/fluorouracil (5FU).[5,6,7,8,9,10,11,12]

Evidence (radiation therapy with concomitant chemotherapy):

Five randomized, phase III trials have shown an overall survival (OS) advantage for cisplatin-based therapy given concurrently with radiation therapy,[5,6,7,8,9,10] but one trial that examined this regimen demonstrated no benefit.[13] The patient populations in these studies included women with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.

Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.

The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.

Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[14,15]

In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[16,17,18][Level of evidence: 1iiDii]

In an attempt to improve upon standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stages IIB to IVA cervical cancer.[19][Level of evidence: 1iiA] A total of 515 patients from nine countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks with concurrent EBRT (50.4 Gy in 28 fractions) followed by brachytherapy (30–35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent EBRT and brachytherapy as described for the experimental arm.

A subgroup analysis showed an increased benefit in patients with a higher stage of disease (stages III–IVA vs. stage IIB), which suggested that the increased toxic effects of the experimental protocol may be justified for these patients.[20] Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and to determine quality of life during and after treatment, a condition that was omitted from the protocol.

The addition of adjuvant chemotherapy following chemoradiation therapy is currently being evaluated as part of a large multinational clinical trial. The OUTBACK trial (NCT01414608) is randomly assigning women to receive cisplatin (40 mg/m2 weekly for 5 doses) with whole-pelvic radiation therapy (standard chemoradiation therapy) with or without standard chemoradiation therapy plus adjuvant carboplatin (AUC 5 + paclitaxel 155 mg/m2).

Lymph Node Management

Patients who are surgically staged as part of a clinical trial and are found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[21] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3.[22] A single study (RTOG-7920) showed a survival advantage in patients who received radiation therapy to para-aortic nodes without histologic evidence of disease.[23] Toxic effects are greater with para-aortic radiation than with pelvic radiation alone but were mostly confined to patients with previous abdominopelvic surgery.[23]

If postoperative EBRT is planned following surgery, extraperitoneal lymph–node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[24] Patients who underwent extraperitoneal lymph–node sampling had fewer bowel complications than those who had transperitoneal lymph–node sampling.[22,24,25]

The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[26] In addition, prospective data points to improvement in outcomes for patients who undergo resection of positive para-aortic lymph nodes before curative intent chemoradiation therapy; however, only patients with minimal nodal involvement (<5mm) benefited.[27]

Other Treatment Options

Interstitial brachytherapy.

Neoadjuvant chemotherapy.

Interstitial brachytherapy

For patients who complete EBRT and have bulky cervical disease such that standard brachytherapy cannot be placed anatomically, interstitial brachytherapy has been used to deliver adequate tumoricidal doses with an acceptable toxicity profile.[28]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[29,30,31,32,33] Multiple regimens have been used; however, almost all utilize a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[34] As a result, although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary endpoint, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IIB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks has been the regimen most often used to treat recurrent cervical cancer since the drug was initially introduced in the 1970's.[2] More recently, the GOG has reported on sequential randomized trials dealing with combination chemotherapy for stages IVB, recurrent, or persistent cervical cancer.[8,12,13,14,15,16]

Evidence (cisplatin in combination with other drugs):

GOG-110, GOG-0179, GOG-0169:

GOG 110: The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary endpoint of response rates, but at the cost of increased toxicity.

GOG 0179: The cisplatin + topotecan (CT) doublet combination had a significant advantage in overall survival (OS) compared with cisplatin alone, leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.[12]

GOG 0169: The paclitaxel + cisplatin (PC) combination, similarly, was superior in response rates and progression-free survival (PFS), and its toxicity was similar to that of the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic–4, totally bedridden). Therefore, PC was chosen as the reference arm in GOG-0204 (NCT00064077).

GOG-0204 enrolled 513 patients and compared four cisplatin-based doublet regimens. The trial was closed early because no one experimental arm was likely to significantly lower the hazard ratio of death relative to PC:[16]

The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced,[16] but none of the patients in the study arms differed in health-related quality of life during treatment.[17] However, there were more neurologic side effects for PC.

GOG-0240 (NCT00803062) was designed to answer the following two questions:[18]

Can a nonplatinum combination show improvement over the standard of cisplatin-paclitaxel in this population that was previously treated with cisplatin during radiation therapy?

Can the addition of bevacizumab improve combination chemotherapy in patients with stages IVB, persistent, or recurrent cervical cancer?

Treatment options under clinical evaluation for stage IVB cervical cancer include the following:

New anticancer drugs in phase I and phase II clinical trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IVB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks has been the regimen most often used to treat recurrent cervical cancer since the drug was initially introduced in the 1970's.[2] More recently, the GOG has reported on sequential randomized trials dealing with combination chemotherapy for stage IVB, recurrent, or persistent cervical cancer.[9,12,14,15,16,17]

Evidence (cisplatin in combination with other drugs):

GOG-110, GOG-0179, GOG-0169 (NCT00803062)

GOG 110: The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary endpoint of response rates, but at the cost of increased toxicity.

GOG 0179: The cisplatin + topotecan (CT) doublet combination had a significant advantage in overall survival (OS) compared with cisplatin alone, leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.[12]

GOG 0169: The paclitaxel + cisplatin (PC) combination, similarly, was superior in response rates and progression-free survival (PFS), and its toxicity was similar to that of the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic–4, totally bedridden). Therefore, paclitaxel plus cisplatin (PC) was chosen as the reference arm in GOG-0204 (NCT00064077).

GOG-0204 enrolled 513 patients and compared four cisplatin-based doublet regimens. The trial was closed early because no one experimental arm was likely to significantly lower the hazard ratio of death relative to PC:[17]

The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced,[17] but none of the patients in the study arms differed in health-related quality of life during treatment.[18] However, there were more neurologic side effects for PC.

GOG-0240 (NCT00803062) was designed to answer the following two questions:[19]

Can a nonplatinum combination show improvement over the standard of cisplatin-paclitaxel in this population previously treated with cisplatin during radiation therapy?

Can the addition of bevacizumab improve upon combination chemotherapy in patients with stage IVB, persistent or recurrent cervical cancer?

The addition of bevacizumab was well tolerated and showed no difference in quality of life between the two groups.

Patients on bevacizumab were more likely to have grade 3 or higher fistulae (6% vs. 0%), and grade 3 or higher thromboembolic events (8% vs. 1%) compared with patients on chemotherapy alone.

As a result, the addition of bevacizumab may be considered for this patient population.

Pelvic exenteration

No standard treatment is available for patients with recurrent cervical cancer that has spread beyond the confines of a radiation or surgical field. For locally recurrent disease, pelvic exenteration can lead to a 5-year survival rate of 32% to 62% in selected patients.[20,21] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.

Treatment options under clinical evaluation for recurrent cervical cancer include the following:

New anticancer drugs in phase I and phase II clinical trials.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Cervical Cancer During Pregnancy

During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, although expert colposcopy is recommended to exclude invasive cancer.

Diagnosis

Treatment of cervical cancer in pregnancy is predicated on the extent of disease and the gestational age at diagnosis. Patients should undergo biopsy as needed and imaging to establish the extent of disease to make the most informed choices. The most appropriate imaging modality in pregnancy is magnetic resonance imaging, when indicated.

Treatment for Stage I Disease

Pregnancy does not alter the course of cervical cancer. As a result, in certain cases, patients may elect to postpone treatment until its effects on the pregnancy are minimized. This may be considered for patients with the more common, and less aggressive histologic subtypes: squamous, adenocarcinoma, and adenosquamous. Patients with high-risk subtypes, such as small cell or neuroendocrine tumors, should be counseled toward immediate treatment despite the effects on the fetus, given their risk of progression.

Patients with early stage (IA) disease may safely undergo fertility-sparing treatments including cervical conization or radical trachelectomy, as indicated. The optimal timing for this procedure is in the second trimester, before viability. Some authors have suggested waiting until the completion of a pregnancy to initiate treatment.[1] For patients with IA2 and IB disease such a delay may also be safe, but because of a risk of lymphatic spread, assessment of lymph-node status should first be ascertained. The status is best determined surgically via a laparoscopic or open lymph-node dissection, which can be safely performed up to approximately 20 weeks of pregnancy.[2,3] In patients without lymphatic spread, waiting for fetal viability to initiate treatment is an option. Patients with positive lymph nodes should be counseled toward immediate treatment.

Treatment for Stages II, III, and IV Disease

For patients with stage II or greater disease, waiting for viability is generally not acceptable.[4] The standard of care is curative intent chemotherapy and radiation therapy. This treatment is toxic to the fetus and without ovarian transposition will render the ovaries nonfunctional after treatment. Evacuation of the fetus should be performed before the initiation of radiation. When this is not possible, the radiation will generally cause a spontaneous abortion 3 to 5 weeks after initiating treatment.

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy has been offered to patients with locally advanced disease as a way to initiate treatment while maintaining the pregnancy.[1] Most chemotherapy agents can be initiated safely in the second trimester of pregnancy and beyond; mild growth restriction of the fetus is the most common side effect. Restriction of growth has been reported in a relatively small number of patients, and data is lacking on long-term outcomes for these women; as a result, this strategy should be considered with caution. Most of the patients in the reports underwent standard treatment (either surgery or radiation) after completion of the pregnancy.

Changes to This Summary (02 / 04 / 2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Cervical Cancer Treatment

Updated statistics with estimated new cases and deaths for 2016 (cited American Cancer Society as reference 2).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of cervical cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Cervical Cancer Treatment are:

Leslie R. Boyd, MD (New York University Medical Center)

Franco M. Muggia, MD (New York University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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